The misfolding, amyloid aggregation, and fibril formation of intrinsically disordered proteins/peptides (or amyloid proteins) have been shown to cause a number of disorders. The underlying mechanisms of amyloid fibrillation and structural properties of amyloidogenic precursors, intermediates, and amyloid fibrils have been elucidated in detail; however, in-depth examinations on physiologically relevant contributing factors that induce amyloidogenesis and lead to cell death remain challenging. A large number of studies have attempted to characterize the roles of biomembranes on protein aggregation and membrane-mediated cell death by designing various membrane components, such as gangliosides, cholesterol, and other lipid compositions, and by using various membrane mimetics, including liposomes, bicelles, and different types of lipid-nanodiscs. We herein review the dynamic effects of membrane curvature on amyloid generation and the inhibition of amyloidogenic proteins and peptides, and also discuss how amyloid formation affects membrane curvature and integrity, which are key for understanding relationships with cell death. Small unilamellar vesicles with high curvature and large unilamellar vesicles with low curvature have been demonstrated to exhibit different capabilities to induce the nucleation, amyloid formation, and inhibition of amyloid-β peptides and α-synuclein. Polymorphic amyloidogenesis in small unilamellar vesicles was revealed and may be viewed as one of the generic properties of interprotein interaction-dominated amyloid formation. Several mechanical models and phase diagrams are comprehensively shown to better explain experimental findings. The negative membrane curvature-mediated mechanisms responsible for the toxicity of pancreatic β cells by the amyloid aggregation of human islet amyloid polypeptide (IAPP) and binding of the precursors of the semen-derived enhancer of viral infection (SEVI) are also described. The curvature-dependent binding modes of several types of islet amyloid polypeptides with high-resolution NMR structures are also discussed.

Background: Aggregation and fibrillation of amyloid ␤ peptides (A␤) in lipid bilayers lead to membrane disruption. Results: Small vesicles accelerated A␤ fibrillation, whereas large vesicles promoted amorphous aggregation. Conclusion: Moderate membrane-curvature-dependent interaction is an important factor for A␤ aggregation. Significance: Two types of membrane binding, one leading to amyloid nucleation and the other to non-productive binding, may be common to various amyloidogenic proteins.

Amyloid fibrillation causes serious neurodegenerative diseases and amyloidosis; however, the detailed mechanisms by which the structural states of precursor proteins in a lipid membrane-associated environment contribute to amyloidogenesis still remains to be elucidated. We examined the relationship between structural states of intrinsically-disordered wild-type and mutant α-synuclein (αSN) and amyloidogenesis on two-types of model membranes. Highly-unstructured wild-type αSN (αSN) and a C-terminally-truncated mutant lacking negative charges (αSN) formed amyloid fibrils on both types of membranes, the model membrane mimicking presynaptic vesicles (Mimic membrane) and the model membrane of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC membrane). Unstructured αSN and αSN both bound to Mimic membranes in a helical conformation with similar binding affinity. Promotion and then inhibition of amyloidogenesis of αSN were observed as the concentration of Mimic lipids increased. We explain this by the two-state binding model: at lower lipid concentrations, binding of αSN to membranes enhances amyloidogenicity by increasing the local concentration of membrane-bound αSN and so promoting amyloid nucleation; at higher lipid concentrations, membrane-bound αSN is actually in a sense diluted by increasing the number of model membranes, which blocks amyloid fibrillation due to an insufficient bound population for productive nucleation. Meanwhile, αSN formed amyloid fibrils over the whole concentration of Mimic lipids used here without inhibition, revealing the importance of helical structures for binding affinity and negatively charged unstructured C-terminal region for modulating amyloidogenesis. We propose that membrane binding-induced initial conformations of αSN, its overall charge states, and the population of membrane-bound αSN are key determinants of amyloidogenesis on membranes.

We herein report the mechanism of amyloid formation of amyloid-β (Aβ) peptides on small (SUV) and large unilamellar vesicles (LUVs), which consist of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. Although Aβ formed fibrils on SUVs at all POPC concentrations used, the lag time, elongation rate, maximum thioflavin T intensity, and fibrillar morphology were distinct, indicating polymorphic amyloid formation. LUVs, at low POPC concentrations, did not markedly affect fibrillation kinetics; however, increases in POPC concentrations suppressed amyloid formation. No significant differences in the thermal stabilities of Aβ fibrils formed with and without vesicles were observed, although fibrils formed on SUVs showed some differences with dilution. SUVs markedly promoted Aβ fibrillation by condensing Aβ, whereas no effects of LUVs on amyloidogenesis were detected. Salts greatly increased Aβ amyloidogenicity on vesicles. We proposed comprehensive models for vesicle size-dependent Aβ amyloidogenesis. Inhomogeneous packing defects in SUVs may induce distinct nucleation in the polymorphisms of amyloids and decreasing local concentrations of Aβ with higher amounts of LUVs inhibits amyloid formation. We also pointed out that C-terminal hydrophobicity of Aβ is important for amyloidogenesis on membranes.